Cellular growth and differentiation appear to be initiated, promoted, maintained, and regulated by a multiplicity of stimulatory, inhibitory, and synergistic factors and hormones. The alteration and/or breakdown of the cellular homeostasis mechanism seems to be a fundamental cause of growth related diseases, including neoplasia. Growth modulatory factors are implicated in a wide variety of pathological and physiological processes including signal transduction, cell communication, growth and development, embryogenesis, immune response, hematopoiesis, cell survival and differentiation, inflammation, tissue repair and remodeling, atheroscleorosis and cancer. Justifiably, there is a great deal of interest in isolating, characterizing, and defining the functional mechanisms of growth modulatory factors because of their potential use in the diagnosis, prognosis, and treatment of cancer. Moreover, acquiring knowledge of these factors will aid in the understanding of the basic mechanisms behind normal growth control and the loss thereof in cancer cells.
Epidermal growth factor (EGF), transforming growth factor-.alpha. (TGF.alpha.), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), nerve growth factor (NGF), transforming growth factor-.beta. (TGF.beta.), insulin growth factor I and II (IGF I, IGF II), hematopoietic growth factors such as erythropoietin, colony stimulating factors (CSF 1 and 2), interleukins (IL-1 to 6), interferons (IFN .alpha., .beta., .gamma.), tumor necrosis factor .alpha. and .beta. (TNF .alpha., .beta.), leukoregulin, oncostatin M, and other less defined factors are growth and differentiation modulatory proteins produced by a variety of cell types either under normal physiological conditions or in response to exogenous stimuli. Most of these factors appear to act in autocrine and paracrine fashions. (For reviews see: Goustin, et al., 1986, Cancer Res. 46: 1015-1029; Rozengurt, 1986, Science 234: 161-66; Pardee, 1987, Cancer Res. 47: 1488-1491; Sachs, 1986, Sci. Amer. 254: 40-47; Marshall, 1987, Cell 50: 5-6; Melcher and Anderson, 1987, Cell 30: 715-720; Clemens and McNurlan, 1985, Biochem. J. 226: 345-360; Nathan, 1987, J. Clin. Invest. 79: 319-326; Sporn and Roberts, 1986, J. Clin. Invest. 78: 329-332; Old, 1987, Nature, 326: 330-331; Beutler and Cerami, 1987, New Eng. J. Med. 316: 379-385; Weinstein, J. Cell. Biochem., 33: 213-224; Zarling, et al., 1987, Proc. Natl. Acad. Sci. U.S.A. 83: 9739-9744; Sporn and Todaro, 1985, N. Eng. J. Med. 303: 878-880; Sporn and Roberts, 1985, Nature 313:, 745-747).
Biologically active phorbol esters such as 12-0-tetradecanoyl-phorbol-13-acetate (TPA) are potent tumor-promoters in vivo and elicit and modulate a wide variety of biological and biochemical responses in vivo as well as in vitro (Blumberg, 1981, Crit. Rev. Toxicol. 9: 153-197; Slaga, 1983, Cancer Surv. 2: 595-612). It has been known for some time that TPA inhibits the growth of the human breast adenocarcinoma cell line MCF-7. In addition, TPA also alters the morphology of MCF-7 cells inasmuch as TPA treated cells exhibit the morphological characteristics of secretory cells (Osborne, et al., 1981, J. Clin. Invest. 67: 943-951; Valette et al., 1987, Cancer Res. 47: 1615-1620).